The search for new therapeutic agents has been greatly aided in recent years by a better understanding of the structure of proteins and other biomolecules associated with target diseases. One important class of proteins is the sigma (σ) receptor, a cell surface receptor of the central nervous system (CNS) which may be related to the dysphoric, hallucinogenic and cardiac stimulant effects of opioids. From studies of the biology and function of sigma receptors, evidence has been presented that sigma receptor ligands may be useful in the treatment of psychosis and movement disorders such as dystonia and tardive dyskinesia, and motor disturbances associated with Huntington's chorea or Tourette's syndrome and in Parkinson's disease (Walker, J., et al, Pharmacol. Rev. 1990; 42:355). It has been reported that the known sigma receptor ligand rimcazole clinically shows effects in the treatment of psychosis (Snyder, S., Largent, B., J. Neuropsychiatry 1989; 1:7). The sigma binding sites have preferential affinity for the dextrorotatory isomers of certain opiate benzomorphans, such as (+)SKF 10047, (+)cyclazocine, and (+)pentazocine and also for some narcoleptics such as haloperidol. Several sigma receptor ligands are disclosed in the prior art.
Patent application WO 2006/021462 discloses a family of pyrazol derivatives which are particularly selective as inhibitors of the sigma receptor. Said derivatives show a pyrazol group which is characterized by the substitution, at position 3, with an alkoxy group bounded to a nitrogen atom. These compounds have displayed strong analgesic activity in the treatment and prevention of chronic and acute pain and, particularly, neuropathic pain.
However, compounds disclosed in WO 2006/021462 have shown poor rheological properties and poor compressibility characteristics. This makes difficult to formulate them, since mechanical operations are normally applied on the compositions comprising the active ingredient, and good compressibility and rheological properties facilitate the handling and manufacture of the formulation.
In addition, the preparation of formulations with high load of active ingredient is not without problems. Formulations typically contain more than 20% of excipients by weight of the total formulation. This is necessary for the successful production of forms such as pellets which involves several mechanical steps, and optionally the use of a binder (Hileman, G., et al, Int. J. Pharma. 1993; 100(1-3):71-79; Jover, I., et et al, J. Pharma. Sci. 1996; 85:700-705). In particular diluents, binders and plasticizers play an important role in the properties of the final product, such as plastic characteristics of the solid formulation, necessary to obtain particles with the desired shapes, uniform size and good handling and dissolution properties.
For example, it is believed that microcrystalline cellulose (MCC), a usual diluent, acts as a molecular sponge by holding water applied during the wet massing step until pressure is applied (by extrusion or spheronization forces) that causes the held water to be expressed to the particle surface. The water present at the surface of the particles acts as a lubricant, reducing the shear forces of extrusion and thus assisting in the formation of cylindrical extrudate from the wetted mass. The water remaining inside the extrudate acts as a plasticizer in that it allows the MCC to be less structurally rigid during spheronization.
Unfortunately, the need to use certain amounts of excipients, such as diluents, limits the active load in the final formulation.
In general, the prevention and treatment of pain require formulations that enable the fast delivery of the analgesic agent to the patient. In addition, the development of pain often demands that a high dosage of the analgesic agent be administered immediately after or before the pain onset. Most patients usually experience episodes of high intensity pain at this juncture. Consequently, there is a need in the art for better formulations of the compounds described in WO 2006/021462 that would also enable a higher load of the active ingredient.